title: Mutations in SH3PXD2B cause Borrone dermato-cardio-skeletal syndrome.
abstract: Borrone Dermato-Cardio-Skeletal (BDCS) syndrome is a severe progressive autosomal recessive disorder characterized by coarse facies, thick skin, acne conglobata, dysmorphic facies, vertebral abnormalities and mitral valve prolapse. We identified a consanguineous kindred with a child clinically diagnosed with BDCS. Linkage analysis of this family (BDCS1) identified five regions homozygous by descent with a maximum LOD score of 1.75. Linkage analysis of the family that originally defined BDCS (BDCS3) identified an overlapping linkage peak at chromosome 5q35.1. Sequence analysis identified two different homozygous mutations in BDCS1 and BDCS3, affecting the gene encoding the protein SH3 and PX domains 2B (SH3PXD2B), which localizes to 5q35.1. Western blot analysis of patient fibroblasts derived from affected individuals in both families demonstrated complete loss of SH3PXD2B. Homozygosity mapping and sequence analysis in a second published BDCS family (BDCS2) excluded SH3PXD2B. SH3PXD2B is required for the formation of functional podosomes, and loss-of-function mutations in SH3PXD2B have recently been shown to underlie 7 of 13 families with Frank-Ter Haar syndrome (FTHS). FTHS and BDCS share some overlapping clinical features; therefore, our results demonstrate that a proportion of BDCS and FTHS cases are allelic. Mutations in other gene(s) functioning in podosome formation and regulation are likely to underlie the SH3PXD2B-mutation-negative BDSC/FTHS patients.
authors.affiliation: 1] Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, The Royal Children's Hospital, Flemington Road, Melbourne, VIC, Australia [2] Department of Paediatrics, The University of Melbourne, Melbourne, VIC, Australia.
authors.forename: Gabrielle R
authors.initials: GR
authors.lastname: Wilson
authors.affiliation: Bioinformatics Division, The Walter and Eliza Hall Institute, Melbourne, VIC, Australia.
authors.forename: Jasmine
authors.initials: J
authors.lastname: Sunley
authors.affiliation: 1] Bioinformatics Division, The Walter and Eliza Hall Institute, Melbourne, VIC, Australia [2] Department of Medical Biology, The University of Melbourne, Melbourne, VIC, Australia.
authors.forename: Katherine R
authors.initials: KR
authors.lastname: Smith
authors.affiliation: Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, The Royal Children's Hospital, Flemington Road, Melbourne, VIC, Australia.
authors.forename: Kate
authors.initials: K
authors.lastname: Pope
authors.affiliation: Bioinformatics Division, The Walter and Eliza Hall Institute, Melbourne, VIC, Australia.
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Bromhead
authors.affiliation: Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, The Royal Children's Hospital, Flemington Road, Melbourne, VIC, Australia.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Fitzpatrick
authors.affiliation: Unit of Rare Diseases, Department of Pediatrics, Istituto Giannina Gaslini, Genoa, Italy.
authors.forename: Maja
authors.initials: M
authors.lastname: Di Rocco
authors.affiliation: Department of Dermatology, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Maurice
authors.initials: M
authors.lastname: van Steensel
authors.affiliation: Department of Metabolic Medicine, The Royal Children's Hospital, Brisbane, QLD, Australia.
authors.forename: David J
authors.initials: DJ
authors.lastname: Coman
authors.affiliation: 1] Department of Paediatrics, The University of Melbourne, Melbourne, VIC, Australia [2] Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, VIC, Australia [3] Department of Neurology, Royal Children's Hospital, Melbourne, VIC, Australia.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Leventer
authors.affiliation: 1] Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, The Royal Children's Hospital, Flemington Road, Melbourne, VIC, Australia [2] Department of Paediatrics, The University of Melbourne, Melbourne, VIC, Australia [3] Department of Clinical Genetics, Austin Health, Heidelberg, VIC, Australia.
authors.forename: Martin B
authors.initials: MB
authors.lastname: Delatycki
authors.affiliation: 1] Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, The Royal Children's Hospital, Flemington Road, Melbourne, VIC, Australia [2] Department of Paediatrics, The University of Melbourne, Melbourne, VIC, Australia.
authors.forename: David J
authors.initials: DJ
authors.lastname: Amor
authors.affiliation: 1] Bioinformatics Division, The Walter and Eliza Hall Institute, Melbourne, VIC, Australia [2] Department of Mathematics and Statistics, The University of Melbourne, Melbourne, VIC, Australia.
authors.forename: Melanie
authors.initials: M
authors.lastname: Bahlo
authors.affiliation: 1] Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, The Royal Children's Hospital, Flemington Road, Melbourne, VIC, Australia [2] Department of Paediatrics, The University of Melbourne, Melbourne, VIC, Australia.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Lockhart
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D003241:Consanguinity; D019465:Craniofacial Abnormalities / Q000473:pathology; D005260:Female; D006801:Humans; D017880:Limb Deformities, Congenital / Q000473:pathology; D008297:Male; D008945:Mitral Valve Prolapse / Q000473:pathology; D009154:Mutation; D010375:Pedigree; D012868:Skin Abnormalities / Q000473:pathology; D013577:Syndrome
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C547814:SH3PXD2B protein, human